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WO2004060308A2 - Thiosemicarbazones antiviraux et immunostimulants - Google Patents

Thiosemicarbazones antiviraux et immunostimulants Download PDF

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Publication number
WO2004060308A2
WO2004060308A2 PCT/US2003/041493 US0341493W WO2004060308A2 WO 2004060308 A2 WO2004060308 A2 WO 2004060308A2 US 0341493 W US0341493 W US 0341493W WO 2004060308 A2 WO2004060308 A2 WO 2004060308A2
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alkyl
compound
absent
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PCT/US2003/041493
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English (en)
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WO2004060308A3 (fr
Inventor
Paul Barsanti
Nathan Brammeier
Anthony Diebes
Liana Lagniton
Simon Ng
Zhi-Jie Ni
Keith B. Pfister
Casey Philbin
Nicholas Valiante
Allan Wagman
Weibo Wang
Amy Weiner
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Novartis Vaccines and Diagnostics Inc
Original Assignee
Chiron Corp
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Priority to EP03800284A priority Critical patent/EP1587473A4/fr
Priority to AU2003300021A priority patent/AU2003300021A1/en
Priority to CA002511646A priority patent/CA2511646A1/fr
Publication of WO2004060308A2 publication Critical patent/WO2004060308A2/fr
Anticipated expiration legal-status Critical
Publication of WO2004060308A3 publication Critical patent/WO2004060308A3/fr
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A61K31/175—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine having the group, >N—C(O)—N=N— or, e.g. carbonohydrazides, carbazones, semicarbazides, semicarbazones; Thioanalogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D209/80—[b, c]- or [b, d]-condensed
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    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C07D211/28—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms to which a second hetero atom is attached
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants

Definitions

  • This invention relates to compounds and compositions, as well as uses of the compounds as imniunopotentiators and use of the compounds in methods for treating and preventing viral infections including HCV. More particularly, the invention relates to compounds that are used alone or combined with other agents for which the immune response is desired, in the treatment or modulation of cancer, allergic diseases, asthma, as well as amelioration of viral, bacterial, and fungal infections. BACKGROUND OF THE INVENTION
  • toxins lipids, proteins/peptides, carbohydrates and nucleic acids
  • other mammalian-derived immunostimulatory molecules e.g. heat shock proteins, complement, immune complexes and proteoglycans
  • heat shock proteins e.g. heat shock proteins, complement, immune complexes and proteoglycans
  • Hepatitis is a systemic disease, which predominantly affects the liver.
  • the disease is typified by the initial onset of symptoms such as anorexia, nausea, vomiting, fatigue, malaise, arthralgias, myalgias, and headaches, followed by the onset of jaundice.
  • the disease may also be characterized by increased serum levels of the aminotransferases AST and ALT. Quantification of these enzymes in serum indicates the extent of liver damage.
  • HBV hepatitis A virus
  • HBV hepatitis B virus
  • NANB non-A, non-B
  • C blood-borne
  • E enterically transmitted
  • D HBV-associated delta agent
  • hepatitis There are two general clinical categories of hepatitis, acute hepatitis and chronic hepatitis. Symptoms for acute hepatitis range from asymptomatic and non-apparent to fatal infections. The disease may be subclinical and persistent, or rapidly progress to chronic liver disease with cirrhosis, and in some cases, to hepatocellular carcinoma. Acute hepatitis B infection in adult Caucasians in the United States progresses to chronic hepatitis B in about 5% to 10% of the cases. In the remainder of the cases, approximately 65% are asymptomatic. In the Far East, infection is usually perinatal, and 50% to 90% progress to the chronic state.
  • RNA virus This virus (designated "hepatitis C") has no homology with HBV, retroviruses, or other hepatitis viruses.
  • Hepatitis C appears to be the major cause of post-transfusion and sporadic non-A, non-B (NANB) hepatitis worldwide, and plays a major role in the development of chronic liver disease, including hepatocellular carcinoma (Kuo et al., Science 244:362-364, 1989; Choo et al., British Medical Bulletin 46(2) :423 -441, 1990).
  • hepatocellular carcinoma Kermangio et al., Science 244:362-364, 1989; Choo et al., British Medical Bulletin 46(2) :423 -441, 1990.
  • at least one-half will develop chronic hepatitis C.
  • hepatocellular carcinoma A disease related to hepatitis B and hepatitis C infections is hepatocellular carcinoma. Briefly, hepatocellular carcinoma is the most common cancer worldwide. It is responsible for approximately 1,000,000 deaths annually, most of them in China and in sub- Saharan Africa. There is strong evidence of an etiologic role for hepatitis B infection in hepatocellular carcinoma. Carriers of the HBV are at greater than 90 times higher risk for the development of hepatocellular carcinoma than noncarriers. In many cases, hepatitis B virus DNA is integrated within the cellular genome of the tumor.
  • hepatitis C virus has also recently been found to be associated with hepatocellular carcinoma, based upon the observation that circulating HCV antibodies can be found in some patients with hepatocellular carcinoma.
  • surgical resection offers the only treatment for hepatocellular carcinoma, as chemotherapy, radiotherapy, and immunotherapy have not shown much promise (Colombo et al, Lancet 1006-1008, 1989; Bisceglie et al, Ann. of Internal Med. 108:390-401, 1988; Watanabe et al., Int. J. Cancer 48:340-343, 1991; Bisceglie et al, Amer. J. Gastro. 86:335-338, 1991).
  • the invention provides novel immune potentiators, novel vaccine adjuvants, novel compounds and pharmaceutical compositions, novel methods for treating viral infections, including HCV, by administering the compounds, and novel methods for modulating the immune response by administering the compounds.
  • the compounds used in the methods and compositions of the invention are small molecules.
  • the compounds are combined with numerous antigens and delivery systems to form a final vaccine product.
  • the compounds are used alone or combined with agents or other therapies for which the immune response is desired for treatment or modulation of cancer, allergic diseases, asthma, and chronic infections such as coronavirus,
  • SARS-associated coronavirus SARS-CoV
  • HIV SARS-associated coronavirus
  • HCV HBV
  • HSV H. pylori
  • One embodiment of the invention is a composition comprising:
  • a vaccine in an amount effective to stimulate a cell-mediated immune response
  • a vaccine adjuvant comprising a thiosemicarbazone or derivative thereof, in an amount effective to potentiate the cell-mediated immune response to the vaccine.
  • the nvention is an composition according to claim 1, wherein the thiosemicarbazone is a compound of formula I:
  • E is absent or selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteroaryl;
  • L is absent or is selected from the group consisting of oxo, amino, alkylene, substituted alkylene, alkoxy, alkylamino, aminoalkyl, heterocyclyl, carbocyclyl, and carbonyl;
  • W is absent or selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteroaryl;
  • X is absent or is selected from the group consisting of oxo, amino, alkylene, substituted alkylene, alkoxy, alkylamino, aminoalkyl, heterocyclyl, carbocyclyl, and carbonyl;
  • Y is selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteroaryl;
  • Y' is absent or is selected from the group consisting of F, Cl, Br, I, nitro, alkyl, substituted alkyl, and optionally substituted heterocyclyl, amino, alkylamino, dialkylamino;
  • Y" is absent or is selected from the group consisting of F, Cl, Br, I, nitro, alkyl, substituted alkyl, and optionally substituted heterocyclyl, amino, alkylamino, dialkylamino;
  • R' is H, alkyl, or substituted alkyl
  • R" is H, or
  • R' and R' ' are taken together to form a hetercyclic ring
  • Z and Z' are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, alkoxy, substituted alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyl sulfonyl, methanesulfonyl, and substituted or unsubstituted alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, heteroarylcarbonyloxy, heteroaralkylcarbonyloxy, alkylaminocarbonyloxy, arylamino- carbonyloxy, formyl, loweralkylcarbonyl, loweralkoxycarbon
  • Z and Z' are taken together to form a heterocyclic group, which may be optionally substituted;
  • Other embodiments include methods of treating a viral infection comprising the step of administering to a subject a composition as described above.
  • Still other embodiments include a method of treating a viral infection or potentiating a cell-mediated immune response comprising administering to a subject a compound of formula II:
  • W is selected from substituted and unsubstituted aryl, or a substituted and unsubstituted heteroaryl group having one ring or two fused rings;
  • X is absent or is selected from the group consisting of oxo, amino, alkylene, substituted alkylene, alkoxy, alkylamino, aminoalkyl, heterocyclyl, and carbocyclyl, wherein if X is absent, Y and W together form an optionally substituted aryl or heteroaryl group having at least two fused rings; [0047] Y is selected from substituted and unsubstituted aryl, or a substituted and unsubstituted heteroaryl group having one ring or two fused rings;
  • Y' is absent or is selected from the group consisting of F, Cl, Br, I, nitro, alkyl, substituted alkyl, and optionally substituted heterocyclyl, amino, alkylamino, dialkylamino;
  • Y is absent or is selected from the group consisting of F, Cl, Br, I, nitro, alkyl, substituted alkyl, and optionally substituted heterocyclyl, amino, alkylamino, dialkylamino;
  • R' is H or CH 3 ,
  • Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, and optionally substituted heterocyclylalkyl;
  • Still other embodiments include compounds of formula III,
  • W is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heteroaryl groups;
  • X and L are each independently absent or independently selected from the group consisting of lower alkyl and carbonyl;
  • R is absent or selected from the group consisting of carbonyl, amino, alkyl, substituted alkyl, alkylamino, and dialkylamino;
  • Y is an aryl or heteroaryl group
  • Y' is absent or selected from the group consisting of F, Cl, Br, I, alkyl, substituted alkyl, heterocyclyl, amino, alkylamino, dialkylamino, and nitro;
  • Y is absent or selected from the group consisting of F, Cl, Br, I, alkyl, substituted alkyl, heterocyclyl, amino, alkylamino, dialkylamino, and nitro;
  • Z is hydrogen, or if Y is furanyl, then Z may be selected from the group consisting of alkyl, substituted alkyl, heterocyclyl, amino, alkylamino, dialkylamino, and nitro; and [0063] salts, prodrugs, or tautomers thereof.
  • W is an optionally substituted phenyl or pyridinyl group;
  • X is alkoxy or alkylamino;
  • Y' is H or fluoro;
  • Y' is dialkylamino, fluoro, or nitro; and [0070] salts, prodrugs, or tautomers thereof.
  • Another embodiment includes compounds of Formula IVc
  • W is phenyl substituted with at least one member selected from the group consisting of-Cl; -F; -Br; -CF3; -OCH 3 ; -NO 2 ; -CH 3 ; N(CH 3 ) 2 ; and -OCF 3 ;
  • X is alkoxy
  • n is an integer from 1 and 3.
  • Another embodiment includes compounds of Formula V
  • R is an alkyl group; [0079] X is alkoxy; and [0080] salts, prodrugs, or tautomers thereof. [0081] [0082] Still another embodiment includes compounds of Formula VI
  • X is absent or an alkylene
  • Y' is absent or is an alkyl group
  • R is a halogen
  • Another embodiment includes compounds of Formula VII [0089]
  • R is nitro and Z is H;
  • R is Cl and Z is selected from the group consisting of alkyl, pyridylalkylene, piperidinylalkylene, morpholinylalkylene, and piperizinylalkylene ;
  • W is a phenyl, substituted phenyl, pyridinyl, or substituted pyridinyl group
  • X is absent or is selected from the group consisting of oxo, amino, alkylene, and substituted alkylene; and [0098] Y is an aryl or heteroaryl group.
  • Another embodiment includes compounds of formula IX:
  • Y is an aryl or heteroaryl group having one ring or two fused rings; [0102] Y' is selected from the group consisting of halo, nitro, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocyclyl, substituted heterocyclyl, amino, alkylamino, and dialkylamino; and [0103] Y" is absent or is selected from the group consisting of halo, nitro, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, amino, alkylamino, and dialkylamino.
  • Yet another embodiment includes pharmaceutical.
  • Another embodiment includes a method of treating a viral infection comprising administering to a subject a pharmaceutical composition composition comprising a therapeutically effective amount any of the above-mentioned compounds, salts and tautomers thereofe, and a pharmaceutically suitable carrier.
  • the viral infection is HCV.
  • Some embodiments involve a method of treating viral infections in a subject comprising administering to the subject any one or more of the compounds described herein or, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable salt of the tautomer.
  • Still other embodiments involve the methods described above wherein the infection is an HCV infection.
  • Some embodiments of a method of adminstering a vaccine comprise simulatneously administering a vaccine in an amount effective to stimulate a cell- mediated immune response; and a vaccine adjuvant comprising a thiosemicarbazone or derivative thereof, in an amount effective to potentiate the cell-mediated immune response to the vaccine.
  • a method of adminstering a vaccine comprise separately administering a vaccine in an amount effective to stimulate a cell-mediated immune response; and a vaccine adjuvant comprising a thiosemicarbazone or derivative thereof, in an amount effective to potentiate the cell-mediated immune response to the vaccine, wherein the vaccine adjuvant is adminstered either prior to or subsequent to administration of the vaccine.
  • Figure 1 shows candidate small molecule immuno-potentiators identified in vitro by measuring TNF-alpha production by human PBMC.
  • Figure 2 shows thiosemicarbazone cytokine induction at several concentrations.
  • Figure 3 depicts a high throughput assay for small molecule immune potentiator screen.
  • Figure 4 depicts dual functional HCV anti-virals and immune potentiators.
  • One embodiment of the invention is directed to a method of inducing an immunostimulatory effect in a patient comprising administering a thiosemicarbazone compound in an amount effective to stimulate a cell-mediated immune response.
  • One preferred embodiment of the method of inducing an immunostimulatory effect in a patient is directed to a vaccine adjuvant composition comprising a vaccine in an amount effective to stimulate a cell-mediated immune response and, as a vaccine adjuvant, a thiosemicarbazone or derivatives thereof, in an amount effective to potentiate the cell- mediated immune response to the vaccine.
  • a vaccine may be prophylactic and/or therapeutic in nature.
  • the vaccines and vaccine compositions disclosed herein likewise may be used prophylactically or therapeutically.
  • the thiosemicarbazone When administered as a vaccine adjuvant, it may be administered simultaneously with the vaccine, prior to the vaccine, and even after vaccine administration.
  • the thiosemicarbazone is a compound of formula I, the tautomers thereof, and the pharmaceutically acceptable salts, esters, or prodrugs thereof:
  • E is absent or selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteroaryl;
  • L is absent or is selected from the group consisting of oxo, amino, alkylene, substituted alkylene, alkoxy, alkylamino, aminoalkyl, heterocyclyl, carbocyclyl, and arbonyl;
  • W is absent or selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteroaryl;
  • X is absent or is selected from the group consisting og oxo, amino, alkylene, substituted alkylene, alkoxy, alkylamino, aminoalkyl, heterocyclyl, carbocyclyl, and carbonyl;
  • Y is selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteroaryl;
  • Y' is absent or is selected from the group consisting of halo, nitro, alkyl, substituted alkyl, and optionally substituted heterocyclyl, amino, alkylamino, dialkylamino;
  • Y is absent or is selected from the group consisting of halo, nitro, alkyl, substituted alkyl, and optionally substituted heterocyclyl, amino, alkylamino, dialkylamino;
  • R' is H, alkyl, or substituted alkyl
  • R" is H, or
  • R' and R" are taken together to form a heterocyclic ring
  • Z and Z' are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, alkoxy, substituted alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyl sulfonyl, methanesulfonyl, and substituted or unsubstituted alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, heteroarylcarbonyloxy, heteroaralkylcarbonyloxy, alkylaminocarbonyloxy, arylamino- carbonyloxy, formyl, loweralkylcarbonyl, loweralkoxycarbon
  • the above method of inducing an immunostimulatory effect in a patient includes the administration of the thiosemicarbazone compound to enhance the efficacy of a therapeutic treatment by stimulating a local immune response in selected cells or tissues of the patient.
  • the above method of stimulating a local immune response in selected cells or tissues of a patient includes the stimulation of a local immune response wherein the selected cells or tissues are infected or cancerous.
  • the selected cells or tissues are infected with a fungus or bacterium.
  • the selected cells are infected with an allergen.
  • the selected cells are infected with a virus.
  • the virus is the as coronavirus, SARS-associated coronavirus (SARS-CoV), HCV, HIV, HBV, HSV, H. pylori, HSV Type 1 or 2, or Human Papilloma Virus.
  • the vaccine adjuvant compositions of the invention can contain further pharmaceutically acceptable ingredients, excipients, carriers, and the like well known to those skilled in the art.
  • the invention is also directed to administering the vaccine adjuvant composition.
  • the vaccine is administered in an amount effective to stimulate an immune response.
  • the amount that constitutes an effective amount depends, inter alia, on the particular vaccine used, the particular adjuvant compound being administered and the amount thereof, the immune response that is to be enhanced (humoral or cell mediated), the state of the immune system (e.g., suppressed, compromised, stimulated), and the desired therapeutic result. Accordingly it is not practical to set forth generally the amount that constitutes an effective amount of the vaccine. Those of ordinary skill in the art, however, can readily determine the appropriate amount with due consideration of such factors.
  • the vaccine adjuvant compositions of the invention can be administered to animals, e.g., mammals (human and non-human), fowl, and the like according to conventional methods well known to those skilled in the art (e.g., orally, subcutaneously, nasally, topically).
  • Suitable vaccines include, but are not limited to, any material that raises either humoral or cell mediated immune response, or both.
  • Suitable vaccines include live viral and bacterial immunogens and inactivated viral, tumor-derived, protozoal, organism-derived, fungal, and bacterial immunogens, toxoids, toxins, polysaccharides, proteins, glycoproteins, peptides, and the like.
  • Conventional vaccines such as those used in connection with BCG (live bacteria), cholera, plague, and typhoid (killed bacteria), hepatitis B, influenza, inactivated polio, and rabies (inactivated virus), measles, mumps, rubella, oral polio, and yellow fever (live virus), tetanus and diphtheria (toxoids), hemophilus influenzae b, meningococcal, and pneumococcal (bacterial polysaccharides) also can be used.
  • Exemplary experimental subunit immunogens include those related to viral disease such as adenovirus, AIDS, chicken pox, cytomegalovirus, dengue, feline leukemia, fowl plague, hepatitis A, hepatitis B, hepatitis C, HSV-1, HSV-2, hog cholera, influenza A, influenza B, Japanese encephalitis, measles, parainfluenza, rabies, respiratory syncytial virus, rotavirus, wart, and yellow fever.
  • viral disease such as adenovirus, AIDS, chicken pox, cytomegalovirus, dengue, feline leukemia, fowl plague, hepatitis A, hepatitis B, hepatitis C, HSV-1, HSV-2, hog cholera, influenza A, influenza B, Japanese encephalitis, measles, parainfluenza, rabies, respiratory syncytial virus, rotavirus, wart, and yellow fever.
  • antigens for use with the invention include, but are not limited to, those listed below.
  • the number(s) in parenthesis indicate representative resources of the antigen.
  • the resource list follows the antigen list and each resource is incorporated by reference in its entirety.
  • Specific antigens include: a protein antigen from N. meningitides serogroup B
  • OMV outer-membrane vesicle
  • gonorrhoeae (1, 2, 3); an antigen from Chlamydia pneumoniae (17, 18, 19, 20, 21, 22, 23); an antigen from Chlamydia trachomatis (24); an antigen from hepatitis A virus, such as inactive virus (25, 26); an antigen from hepatitis B virus, such as the surface and/or core antigens [e.g. 26, 27]; an antigen from hepatitis C virus (28); an antigen from Bordetella pertussis, such as petussis holotoxin (PT) and filamentous haemagglutinin (FHA) from B.
  • Bordetella pertussis such as petussis holotoxin (PT) and filamentous haemagglutinin (FHA) from B.
  • pertussis optionally also combination with pertactin and/or agglutinogens 2 and 3 (29, 30); a diphtheria antigen, such as a diphtheria toxoid (31 :chapter 3) e.g.
  • the CRM197 mutant 32; a tetanus antigen, such as a tetanus toxioid (31 hapter 4); a protein antigen from Helicobacter pylori such as CagA (33), VacA (33), NAP (34), HopX (5), HopY (35) and/or urease; a saccharide antigen from Haemophilus influenzae B (13); an antigen from Porphyromonas gingivalis (36); polio antigen(s) (37, 38) such as IPV or OPV; rabies antigen(s) (39) such lyophilized inactivated virus (40,
  • RabAvertTM measles, mumps and/or rubella antigens (31: chapters 9, 10, & 11); influenza antigen(s) (31:chapter 19), such as the haemagglutinin and/or neuraminidase surface proteins; an antigen from Moraxella catarrhalis (41); an antigen from Streptococcus agalactiae (group
  • streptococcus 42, 43; an antigen from Streptococcus pyogenes (group A streptococcus)
  • composition may comprise one or more of the above antigens.
  • a saccharide or carbohydrate antigen is used, it is preferably conjugated to a carrier protein in order to enhance immunogenicity (47-6).
  • Preferred carrier proteins are bacterial toxine or toxiods, such as diphtheria or tetanus toxoids.
  • the CRM197 diphtheria toxoid is particularly preferred.
  • Other suitable carrier proteins include the N. meningitides outer membrane protein (57), synthetic peptides (58, 59), heat shock proteins (60), pertussis proteins (61, 62), protein D from H. influenzae (63), toxin A or B from C. difficile (64) etc.
  • a mixture comprises capsular saccharides from both serogroups A and C
  • the ratio (w/w) of MenA saccharide :MenC saccharide is greater than 1 (e.g.
  • Saccharides from different serogroups of N.meningitides may be conjugated to the same or different carrier proteins.
  • Toxic protein antigens may be detoxified where necessary (e.g. detoxification of pertussis toxin by chemical and/or genetic means (30)).
  • a diphtheria antigen is included in the composition it is preferred also to include tetanus antigens and pertussis antigens.
  • a tetanus antigen is included it is preferred also to include diphtheria and pertussis antigens.
  • pertussis antigen is included it is preferred also to include diphtheria and tetanus antigens.
  • the invention provides a method of treating a viral infection in a mammal comprising administering to the mammal a compound of formula II or its salts, prodrugs, or tautomers thereof:
  • W is an aryl, substituted aryl, heteroaryl or substituted heteroaryl group having one ring or two fused rings;
  • X is absent or is selected from the group consisting of oxo, amino, alkylene, substituted alkylene, alkoxy, alkylamino, aminoalkyl, heterocyclyl, and carbocyclyl.
  • X is absent or is selected from the group consisting of piperizinyl, -O(CH 2 )n-; -
  • X is absent or is selected from the group consisting of-CH 2 -O-; -O-CH 2 -; -CH 2 ; -O-; -C(O)O-; -NHCH 2 -; -NHCH 2 CH 2 ; and -OCH 2 CH 2 O-;
  • Y is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl group having one ring or two fused rings.
  • Y is selected from the group consisting of phenyl, furanyl, pyrrolyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, and imidazolyl;
  • X does not exist and Y and W together form an arly, substituted aryl, heteroaryl, or substituted heteroaryl group having at least two fused rings.
  • Y and W together form an unsubstituted or substituted nitrogen-containing fused heteroaryl group having at least two fused rings. More preferably an unsubstituted or substituted quinolinyl, indolyl, benzo[g]indolyl, benzindolyl, or benzofuranyl.
  • Y' is absent or is selected from the group consisting of halo, nitro, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, amino, alkylamino, and dialkylamino.
  • Y' is absent or is selected from the group consisting of halo; -CH 3 ;
  • Y" is absent or is selected from the group consisting of halo, nitro, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, amino, alkylamino, and dialkylamino.
  • R' is H or CH 3 ;
  • Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, and substituted heterocyclylalkyl.
  • Z is preferably hydrogen. In another embodiment, if Y is furanyl, then Z is selected from the group consisting of pyridylalkylene, piperidinylalkylene, morpholinylalkylene, and piperizinylalkylene.
  • W is phenyl or phenyl substituted with at least one member selected from the group consisting of halogen; nitro; alkylamino; dialkylamino; alkyl; trifluoroalkyl; and trifluoroalkylalkoxy, preferably with at least one member selected from the group consisting of-Cl; -F; -Br; -CF 3 ; -OCH 3 ; -NO 2 ; CH 3 ; -N(CH 3 ) 2 ; and -OCF 3 .
  • W is a heteroaryl or substituted heteroaryl selected from the group consisting of furanyl, pyridinyl, pyrrolyl, pyrazolyl, pyrazinyl, thiazolyl, and imidazolyl, preferably pyridinyl.
  • the heteroaryl is preferably substituted with at least one member selected from the group consisting of halogen; nitro; alkylamino; dialkylamino; alkyl; trifluoroalkyl; and trifluoroalkylalkoxy, more preferably at least one member selected from the group consisting of -Cl; -F; -Br; -CF 3 ; -OCH 3 ; -NO 2 ; CH 3 ; -
  • Y is pyrrol
  • the Y' and Y" are alkyl.
  • Y is phenyl
  • Y' is alkoxy
  • Y" is a halogen.
  • Y is pyrazolyl
  • Y' is aryl.
  • Y is alkoxy and Y" is alkyl.
  • Y is pyrrol and Y' and Y" are each -CH 3 , X is absent, and W is phenyl substituted with nitro, dimethylamine, Cl, F, or CH 3 .
  • Z is hydrogen
  • Y is furanyl
  • Y' does not exist
  • X is absent, and W is phenyl substituted with Cl or CF 3 ; or Z is hydrogen, Y is phenyl, Y' is
  • X is -OCH 2 - and W is phenyl substituted with one or two Cl; or Z is hydrogen, Y is phenyl, Y' is nitro, X is -NHCH 2 - and W is phenyl substituted with Cl.
  • the invention provides a method of treating a patient with an HCV infection by administering to the patient a compound of formula II, or its salts, prodrugs, or tautomers thereof as described above.
  • the patient is preferably a mammal, and in some embodiments, a human.
  • the compounds may be injected or taken orally.
  • the invention provides a method of treating a patient with an HCV infection by administering to the patient a compound of formula II, or its salts, prodrugs, or tautomers thereof.
  • R' is H or-CH 3 .
  • W is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl group having one ring or two fused rings.
  • W is phenyl or phenyl substituted with at least one member selected from the group consisting of halogen; nitro; alkylamino; dialkylamino; alkyl; trifluoroalkyl; and trifluoroalkylalkoxy, preferably with at least one member selected from the group consisting of-Cl; -F; -Br; -CF 3 ; -OCH 3 ; -NO 2 ; CH 3 ; - N(CH 3 ) 2 ; and -OCF 3 .
  • X is absent or is selected from the group consisting of oxo, amino, alkylene, substituted alkylene, alkoxy, alkylamino, aminoalkyl, heterocyclyl, and carbocyclyl.
  • Y is an aryl or heteroaryl group having one ring or two fused rings.
  • X does not exist and Y and W together form an aryl, substituted aryl, heteroaryl, or substituted heteroaryl group having at least two fused rings.
  • Y' is absent or is selected from the group consisting of nitro, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, amino, alkylamino, and dialkylamino;
  • Y" is absent or is selected from the group consisting of nitro, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, amino, alkylamino, and dialkylamino;
  • Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, and substituted heterocyclylalkyl.
  • the patient is preferably a mammal, and in some embodiments, a human.
  • the compounds may be injected or taken or
  • the invention is also directed to novel compounds as defined below by formulas III- VII, and salts, prodrugs, or tautomers thereof, as well as pharmaceutical compositions containing the compounds and methods of treating or preventing viral infections, in particular HCV, by administering such compounds to a mammal in need thereof.
  • the invention is also directed to novel compounds defined by formula III and salts, prodrugs, or tautomers thereof:
  • W is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl group.
  • W is phenyl or substituted phenyl. If substituted, phenyl is preferably substituted with at least one member selected from the group consisting of Br, Cl, F, and CF 3 .
  • L and X are each independently absent or independently selected from the group consisting of lower alkyl and carbonyl;
  • R is absent or selected from the group consisting of carbonyl, amino, alkyl, substituted alkyl, alkylamino, and dialkylamino.
  • Y is an aryl or heteroaryl group. Y is preferably selected from the group consisting of phenyl, furanyl, pyrridinyl, pyrrolyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, and imidazolyl. More preferably, Y is phenyl, furanyl, or pyrimidinyl.
  • Y' is absent or selected from the group consisting of halo, alkyl, substituted alkyl, heterocyclyl, amino, alkylamino, dialkylamino, and nitro. If present, Y' is preferably fluro, nitro or piperizinyl.
  • Y" is absent or selected from the group consisting of halo, alkyl, substituted alkyl, heterocyclyl, amino, alkylamino, dialkylamino, and nitro. If present, Y' is preferably fluoro, nitro or piperizinyl.
  • Z is hydrogen, or if Y is furanyl, then Z may be selected from the group consisting of alkyl, substituted alkyl, heterocyclyl, amino, alkylamino, dialkylamino, and nitro.
  • W is phenyl or phenyl substituted with -CF 3 or Cl;
  • W is a phenyl, substituted phenyl, pyridinyl, or substituted pyridinyl group. W is preferably substituted with at least one member selected from the group consisting of -Cl; -
  • X is alkoxy or alkylamino.
  • Y' is dialkylamino,fluro, or nitro.
  • the compound IV is defined as IVa and salts, prodrugs, or tautomers thereof:
  • X is alkoxy, preferably -OCH 2 -.
  • W is phenyl substituted with at least one member selected from the group consisting of -Cl; -F; -Br; -CF 3 ; -OCH 3 ; -NO 2 ; -CH 3 ; -N(CH 3 ) 2 ; and -OCF 3 .
  • the compound IV is defined as IVb and salts, prodrugs, or tautomers thereof:
  • X is alkylamino, preferably -NHCH 2 CH 2 - or -NHCH 2 -.
  • W is pyridinyl or phenyl substituted with at least one member selected from the group consisting of Cl, F, and CF 3 , preferably pyridinyl or phenyl substituted with Cl, F, and CF 3 .
  • the compound IV is defined as IVc and salts, prodrugs, or tautomers thereof:
  • X is alkoxy, preferably -OCH 2 -.
  • W is phenyl substituted with at least one member selected from the group consisting of-Cl; -F; -Br; -CF 3 ; -OCH 3 ; -NO 2 ; -CH 3 ; -N(CH 3 ) 2 ; and -OCF 3 .
  • n is an integer from 1 and 3.
  • the invention is also directed to novel compounds defined by formula V and salts, prodrugs, or tautomers thereof
  • R is an alkyl group, preferably methyl.
  • X is alkoxy, preferably -OCH 2 -; -OCH 2 CH 2 -; -CH 2 O-; or -CH 2 CH 2 O-.
  • the invention is also directed to novel compounds defined by formula VI and salts, prodrugs, or tautomers thereof:
  • X is absent or an alkylene, preferably -CH 2 CH 2 -.
  • Y' is absent or is an alkyl group, preferably Y' is absent or is methyl.
  • R is a halogen, preferably Cl.
  • the invention is also directed to novel compounds defined by formula VII and salts, prodrugs, or tautomers thereof:
  • R is nitro and Z is H; or R is Cl and Z is selected from the group consisting of alkyl, pyridylalkylene, piperidinylalkylene, morpholinylalkylene, and piperizinylalkylene, preferably methyl, pyridylmethylene, piperidinylethylene, mo holinylethylene, piperizinylmethylene, piperizinylethylene, and morpholinylbutylene.
  • the invention is also directed to a vaccine adjuvant composition
  • a vaccine adjuvant composition comprising a vaccine in an amount effective to stimulate a cell-mediated immune response and, as a vaccine adjuvant, a a compound of formulas II through VI or derivatives thereof, in an amount effective to potentiate the cell-mediated immune response to the vaccine.
  • the invention is also directed to novel compounds defined by formula VIII and salts, prodrugs, or tautomers thereof:
  • Y is an aryl or heteroaryl group.
  • Y is preferably selected from the group consisting of phenyl, furanyl, pyrridinyl, pyrrolyl, pyrazolyl, pyrazinyl, thiazolyl, and imidazolyl. More preferably, Y is furanyl.
  • X is absent or is selected from the group consisting of oxo, amino, alkylene, and substituted alkylene. More preferably, X is absent.
  • W is a phenyl, substituted phenyl, pyridinyl, or substituted pyridinyl group. W is preferably substituted with at least one member selected from the group consisting of -Cl; -
  • the invention is also directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formulas III through VIII a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable salt of the tautomer and a pharmaceutically suitable carrier or excipient.
  • the invention also provides a method of treating viral infections, including
  • HCV in a subject comprising administering to the subject a compound of formulas III though
  • the invention also provides a method of treating an HCV infection, in a subject comprising administering to the subject a compound of the following formula (IX), a tautomer of the compound, a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable salt of the tautomer.
  • R' is H or lower alkyl.
  • Y is an aryl or heteroaryl group having one ring or two fused rings.
  • Y is selected from the group consisting of phenyl, furanyl, pyrrolyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, and imidazolyl.
  • Y' is selected from the group consisting of nitro, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocyclyl, substituted heterocyclyl, amino, alkylamino, and dialkylamino.
  • Y" is absent or is selected from the group consisting of halo, nitro, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, amino, alkylamino, and dialkylamino.
  • ATP Adenosine triphosphate
  • BSA Bovine Serum Albumin
  • EDTA Ethylene diamine tetraacetic acid
  • HBTU O-Benzotriazol- 1 -yl-N,N,N' ,N' -tetramethyluronium hexafluorophosphate
  • IC50 value The concentration of an inhibitor that causes a 50 % reduction in a measured activity.
  • NMP N-methylpyrrolidone
  • G Geenneerraallllyy,, r eference to a certain element such as hydrogen or H is meant to include all isotopes of that element.
  • an R group is defined to include hydrogen or H, it also includes deuterium and tritium.
  • absent in reference to a particular substituent means the substuent is not present or, when between two other moieties, the "absent" substituent is a covalent bond therebetween.
  • alkyl refers to alkyl groups that do not contain heteroatoms.
  • phrase includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like.
  • the phrase also includes branched chain isomers of straight chain alkyl groups, including but not limited to, the following which are provided by way of example: -CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -CH(CH 2 CH 3 ) 2 , -C(CH 3 ) 3 , -C(CH 2 CH 3 ) 35 -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 2 CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CH 2 C(CH 2 CH 3 ) 3 , -CH(CH 3 )CH(CH 3 )(CH 2 CH3), -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 CH(CH 3 )(CH 2 CH3), -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )(CH 2 CH3),
  • the phrase also includes cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl and such rings substituted with straight and branched chain alkyl groups as defined above.
  • alkyl groups include primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups.
  • Preferred alkyl groups include straight and branched chain alkyl groups and cyclic alkyl groups having 1 to 12 carbon atoms.
  • the phrase "loweralkyl" refers to an acyclic alkyl group as described above.
  • “Lower” is about 1 to about 8 carbon atoms, preferably about 1 to about 6 carbon atoms.
  • substituted alkyl refers to an alkyl group as defined above in which one or more bonds to a carbon(s) or hydrogen(s) are replaced by a bond to non- hydrogen and non-carbon atoms such as, but not limited to, a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, and ester groups; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N- oxides, imides, and
  • Substituted alkyl groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom is replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • Substituted alkyl groups further include alkyl groups in which one or more bonds to a carbon(s) or hydrogen(s) atoms is replaced by a bond to an aryl, heterocyclyl group, or cycloalkyl group.
  • Preferred substituted alkyl groups include, among others, alkyl groups in which one or more bonds to a carbon or hydrogen atom is/are replaced by one or more bonds to fluorine atoms.
  • Another preferred substituted alkyl group is the trifluoromethyl group and other alkyl groups that contain the trifluoromethyl group.
  • Other preferred substituted alkyl groups include those in which one or more bonds to a carbon or hydrogen atom is replaced by a bond to an oxygen atom such that the substituted alkyl group contains a hydroxyl, alkoxy, or aryloxy group.
  • Still other preferred substituted alkyl groups include alkyl groups that have an amine, or a substituted or unsubstituted alkylamine, dialkylamine, arylamine, (alkyl)(aryl)amine, diarylamine, heterocyclylamine, diheterocyclylamine, (alkyl)(heterocyclyl)amine, or (aryl)(heterocyclyl)amine group.
  • substituted alkenyl has the same meaning with respect to alkenyl groups that substituted alkyl groups had with respect to unsubstituted alkyl groups.
  • a substituted alkenyl group includes alkenyl groups in which a non-carbon or non- hydrogen atom is bonded to a carbon double bonded to another carbon and those in which one of the non-carbon or non-hydrogen atoms is bonded to a carbon not involved in a double bond to another carbon.
  • alkynyl refers to straight and branched chain groups such as those described with respect to alkyl groups as defined above, except that at least one triple bond exists between two carbon atoms. Examples include, but are not limited to -C ⁇ C(H), - C ⁇ C(CH 3 ), -C ⁇ C(CH 2 CH 3 ), -C(H 2 )C ⁇ C(H), -C(H) 2 C ⁇ C(CH 3 ), and -C(H) 2 C ⁇ C(CH 2 CH 3 ) among others.
  • substituted alkynyl has the same meaning with respect to alkynyl groups that substituted alkyl groups had with respect to unsubstituted alkyl groups.
  • a substituted alkynyl group includes alkynyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon triple bonded to another carbon and those in which a non-carbon or non-hydrogen atom is bonded to a carbon not involved in a triple bond to another carbon.
  • heterocyclyl refers to both aromatic and nonaromatic ring compounds including monocyclic, bicyclic, and polycyclic ring compounds such as, but not limited to, quinuclidinyl, containing 3 or more ring members of which one or more is a heteroatom such as, but not limited to, N, O, and S.
  • unsubstituted heterocyclyl includes condensed heterocyclic rings such as benzimidazolyl, it does not include heterocyclyl groups that have other groups such as alkyl or halo groups bonded to one of the ring members as compounds such as 2-methylbenzimidazolyl are substituted heterocyclyl groups.
  • heterocyclyl groups include, but are not limited to: unsaturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms such as, but not limited to pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-l,2,4-triazolyl, lH-l,2,3-triazolyl, 2H-l,2,3-triazolyl etc.), tetrazolyl, (e.g.
  • saturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms such as, but not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl; condensed unsaturated heterocyclic groups containing 1 to 4 nitrogen atoms such as, but not limited to, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl; unsaturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to, oxazolyl, isoxazolyl, oxadiazolyl (e.g.
  • unsaturated 3 to 8 membered rings containing 1 to 3 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, thiazolyl, isothiazolyl, thiadiazolyl (e.g.
  • 1,3-benzodioxoyl, etc. unsaturated 3 to 8 membered rings containing an oxygen atom and 1 to 2 sulfur atoms such as, but not limited to, dihydrooxathiinyl; saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms such as 1,4- oxathiane; unsaturated condensed rings containing 1 to 2 sulfur atoms such as benzothienyl, benzodithiinyl; and unsaturated condensed heterocyclic rings containing an oxygen atom and 1 to 2 oxygen atoms such as benzoxathiinyl.
  • unsaturated 3 to 8 membered rings containing an oxygen atom and 1 to 2 sulfur atoms such as, but not limited to, dihydrooxathiinyl
  • saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms such as 1,4- oxathiane
  • Heterocyclyl groups also include those described above in which one or more S atoms in the ring is double-bonded to one or two oxygen atoms (sulfoxides and sulfones).
  • heterocyclyl groups include tetrahydrothiophene, tetrahydrothiophene oxide, and tetrahydrothiophene 1,1 -dioxide.
  • Preferred heterocyclyl groups contain 5 or 6 ring members.
  • More preferred heterocyclyl groups include morpholine, piperazine, piperidine, pyrrolidine, imidazole, pyrazole, 1,2,3- triazole, 1,2,4-triazole, tetrazole, thiomorpholine, thiomorpholine in which the S atom of the thiomorpholine is bonded to one or more O atoms, pyrrole, homopiperazine, oxazolidin-2- one, pyrrolidin-2-one, oxazole, quinuclidine, thiazole, isoxazole, furan, and tetrahydrofuran.
  • substituted heterocyclyl refers to a heterocyclyl group as defined above in which one of the ring members is bonded to a non-hydrogen atom such as described above with respect to substituted alkyl groups and substituted aryl groups. Examples, include, but are not limited to, 2-methylbenzimidazolyl, 5-methylbenzimidazolyl, 5- chlorobenzthiazolyl, 1 -methyl piperazinyl, and 2-chloropyridyl among others.
  • aryl refers to aryl groups that do not contain heteroatoms.
  • the phrase includes, but is not limited to, groups such as phenyl, biphenyl, anthracenyl, naphthenyl by way of example.
  • aryl includes groups containing condensed rings such as naphthalene, it does not include aryl groups that have other groups such as alkyl or halo groups bonded to one of the ring members, as aryl groups such as tolyl are considered herein to be substituted aryl groups as described below.
  • a preferred unsubstituted aryl group is phenyl. Unsubstituted aryl groups may be bonded to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s), and/or sulfur atom(s) in the parent compound, however.
  • substituted aryl group has the same meaning with respect to unsubstituted aryl groups that substituted alkyl groups had with respect to unsubstituted alkyl groups.
  • a substituted aryl group also includes aryl groups in which one of the aromatic carbons is bonded to one of the non-carbon or non-hydrogen atoms described above and also includes aryl groups in which one or more aromatic carbons of the aryl group is bonded to a substituted and/or unsubstituted alkyl, alkenyl, or alkynyl group as defined herein.
  • a fused ring system e.g. dihydronaphthyl or tetrahydronaphthyl.
  • substituted aryl includes, but is not limited to tolyl, 1,3-dichlorobenzene, and hydroxyphenyl among others.
  • heteroaryl refers to a cyclic or bicyclic aromatic radical having from five to ten ring atoms in each ring of which one atom of the cyclic or bicyclic ring is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and naphthyridinyl, and the like.
  • substituted heteroaryl refers to a heteroaryl group as defined herein substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, C ⁇ -C 3 -alkyl, CrC ⁇ -alkoxy, C C ⁇ -alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
  • any one substituent may be an aryl, heteroaryl, or heterocycloalkyl group.
  • biasing refers to a group or substituent to which two aryl groups, which are not condensed to each other, are bound.
  • exemplary biaryl compounds include, for example, phenylbenzene, diphenyldiazene, 4-methylthio-l-phenylbenzene, phenoxybenzene, (2-phenylethynyl)benzene, diphenyl ketone, (4-phenylbuta-l,3-diynyl)benzene, phenylbenzylamine, (phenylmethoxy)benzene, and the like.
  • Preferred unsubstituted or substituted biaryl groups include: 2-(phenylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide, 1,4-diphenylbenzene, 2,4-dichloro-l-(2-methylphenyl)benzene, N-[4-(2- phenylethynyl)phenyl] -2- [benzylamino] acetamide, and [4-(2-phenylethynyl)phenyl]pyrrole.
  • heteroarylaryl refers to a biaryl group where one of the aryl groups is a heteroaryl group.
  • heteroarylaryl groups include, for example, 2- phenylpyridine, phenylpyrrole, 3-(2-phenylethynyl)pyridine, phenylpyrazole, 5-(2- phenylethynyl)- 1 ,3-dihydropyrimidine-2,4-dione, 4-phenyl- 1 ,2,3-thiadiazole, 2-(2- phenylethynyl)pyrazine, 2-phenylthiophene, phenylimidazole, 3-(2-piperazinylphenyl)furan, 3-(2,4-dichlorophenyl)-4-methylpyrrole, and the like.
  • Preferred unsubstituted or substituted heteroarylaryl groups include: 4-(2,4-dichlorophenyl)-3-methylpyrazole, 5-(2- phenylethynyl)pyrimidine-2-ylamine, 1 -methoxy-4-(2-thienyl)benzene, 2-(3- nitrophenyl)thiophene, (tert-butoxy)-N- [(5 -phenyl(3 -pyridyl))methyl] carboxamide, hydroxy- N-[(5-phenyl(3-pyridyl))methyl]-amide, 2-(phenylmethylthio)pyridine, and benzylimidazole.
  • heteroarylheteroaryl refers to a biaryl group where both of the aryl groups are heteroaryl groups.
  • exemplary heteroarylheteroaryl groups include, for example, 3- pyridylimidazole, 2-imidazolylpyrazine, and the like.
  • Preferred unsubstituted or substituted heteroarylheteroaryl groups include: 2-(4-piperazinyl-3-pyridyl)furan, diethyl(3-pyrazin-2- yl(4-pyridyl))amine, and dimethyl ⁇ 2-[2-(5-methylpyrazin-2-yl)ethynyl](4-pyridyl) ⁇ amine.
  • Optionally substituted refers to the optional replacement of hydrogen with one or more monovalent or divalent radicals.
  • Suitable substitution groups include, for example, hydroxyl, nitro, amino, imino, cyano, halo, thio, thioamido, amidino, imidino, oxo, oxamidino, methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl, alkyl, substituted alkyl, haloloweralkyl, loweralkoxy, haloloweralkoxy, loweralkoxyalkyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, alkylthio, aminoalkyl, cyanoalkyl, benzyl, pyridyl, pyrazolyl, pyrrole, thiophene, imi
  • substitution groups include, for example, hydroxyl, nitro, amino, imino, cyano, halo, thio, thioamido, amidino, imidino, oxo, oxamidino, methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl, alkyl, substituted alkyl, haloloweralkyl, loweralkoxy, haloloweralkoxy, loweralkoxyalkyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, alkylthio, aminoalkyl, cyanoalkyl, benzyl, pyridyl, pyrazolyl, pyrrole, thiophene,
  • amidino and heterocycloamidino groups include, for example, those shown below. These amidino and heterocycloamidino groups can be further substituted as will be apparent to those having skill in the organic and medicinal chemistry arts in conjunction with the disclosure herein.
  • substituted alkylcarbonylamino, alkyloxycarbonylamino, aminoalkyloxycarbonylamino, and arylcarbonylamino groups include, for example, those shown below. These groups can be further substituted as will be apparent to those having skill in the organic and medicinal chemistry arts in conjunction with the disclosure herein.
  • substituted aminocarbonyl groups include, for example, those shown below. These can be further substituted by heterocyclo groups and heteroaryl groups as will be apparent to those having skill in the organic and medicinal chemistry arts in conjunction with the disclosure herein.
  • Prefered aminocarbonyl groups include: N-(2- cyanoethyl)carboxamide, N-(3-methoxypropyl)carboxamide, N-cyclopropyl-carboxamide, N- (2-hydroxy-isopropyl)carboxamide, methyl 2-carbonylamino-3-hydroxypropanoate, N-(2- hydroxypropyl)carboxamide, N-(2-hydroxy-isopropyl)-carboxamide, N- [2-hydroxy- 1 - (hydroxymethyl)ethyl] -carboxamide, N-(2-carbonylaminoethyl)acetamide, N-(2-(2- pyridyl)ethyl)-carboxamide, N-(2-pyridylmethyl)car
  • Representative substituted alkoxycarbonyl groups include, for example, those shown below. These alkoxycarbonyl groups can be further substituted as will be apparent to those having skill in the organic and medicinal chemistry arts in conjunction with the disclosure herein.
  • protected with respect to hydroxyl groups, amine groups, and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction with a protecting group known to those skilled in the art such as those set forth in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999) which can be added or removed using the procedures set forth therein.
  • Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methythiomethyl ether, benzyloxymethyl ether, t- butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethyl ' ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifluoracetate.
  • a reagent such as, but not
  • protected amine groups include, but are not limited to, amides such as, formamide, acetamide, trifluoroacetamide, and benzamide; imides, such as phthalimide, and dithiosuccinimide; and others.
  • protected sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl thioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.
  • a "pharmaceutically acceptable salt” includes a salt with an inorganic base, organic base, inorganic acid, organic acid, or basic or acidic amino acid.
  • the invention includes, for example, alkali metals such as sodium or potassium; alkaline earth metals such as calcium and magnesium or aluminum; and ammonia.
  • the invention includes, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, and triethanolamine.
  • the instant invention includes, for example, hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid.
  • the instant invention includes, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • the instant invention includes, for example, arginine, lysine and ornithine. Acidic amino acids include, for example, aspartic acid and glutamic acid.
  • ester refers to esters, which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • Representative examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
  • prodrugs refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T.
  • allergen refers to a substance (antigen) that can induce an allergic or asthmatic response in a susceptible subject.
  • the list of allergens is enormous and can include pollens, insect venoms, animal dander, dust, fungal spores, and drugs (e.g. penicillin).
  • Asthma refers to a disorder of the respiratory system characterized by inflammation, narrowing of the airways and increased reactivity of the airways to inhaled agents. Asthma is frequently, although not exclusively associated with atopic or allergic symptoms.
  • Immuno-stimulation or “immune potentiation” refers to the increase in cytokine production from a dendritic cell.
  • a "subject” or “patient” is meant to describe a human or vertabrate animal including a dog, cat, horse, cow, pig, sheep, goat, chicken, monkey, rat, and mouse.
  • Suitable pharmaceutically acceptable excipients include processing agents and drug delivery modifiers and enhancers, such as, for example, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl- ⁇ -cyclodextrin, polyvinylpyrrolidinone, low melting waxes, ion exchange resins, and the like, as well as combinations of any two or more thereof.
  • Other suitable pharmaceutically acceptable excipients are described in "Remington: The Science and Practice of Pharmacy ,”Lippincott Williams and Wilkins, Baltimore, Maryland (1995), incorporated herein by reference.
  • compositions containing the compounds of the invention may be in any form suitable for the intended method of administration, including, for example, a solution, a suspension, or an emulsion.
  • Liquid carriers are typically used in preparing solutions, suspensions, and emulsions.
  • Liquid carriers contemplated for use in the practice of the present invention include, for example, water, saline, pharmaceutically acceptable organic solvent(s), pharmaceutically acceptable oils or fats, and the like, as well as mixtures of two or more thereof.
  • the liquid carrier may contain other suitable pharmaceutically acceptable additives such as solubilizers, emulsifiers, nutrients, buffers, preservatives, suspending agents, thickening agents, viscosity regulators, stabilizers, and the like.
  • Suitable organic solvents include, for example, monohydric alcohols, such as ethanol, and polyhydric alcohols, such as glycols.
  • Suitable oils include, for example, soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, and the like.
  • the carrier can also be an oily ester such as ethyl oleate, isopropyl myristate, and the like.
  • Compositions of the present invention may also be in the form of microparticles, microcapsules, liposomal encapsulates, and the like, as well as combinations of any two or more thereof.
  • the compounds of the invention may be administered enterally, orally, parenterally, sublingually, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
  • suitable modes of administration include oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intramuscular, intraperitoneal, intranasal, subdural, rectal, and the like.
  • Topical administration may also involve the use of transdermal administration such as transdermal patches or ionophoresis devices.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-propanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • a suitable nonirritating excipient such as cocoa butter and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
  • the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch.
  • Such dosage forms may also comprise, as is nonnal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
  • Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents.
  • Effective amounts of the compounds of the invention generally include any amount sufficient to detectably treat viral infections.
  • Successful treatment of a subject in accordance with the invention may result in the inducement of a reduction or alleviation of symptoms in a subject afflicted with a medical or biological disorder to, for example, halt the further progression of the disorder, or the prevention of the disorder.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy. The therapeutically effective amount for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician.
  • a therapeutically effective dose will generally be from about 0.1 mg/kg/day to about 1000 mg/kg/day, preferably from about 1 mg/kg/day to about 20 mg/kg/day, which may be administered in one or multiple doses with or without an antigen as described herein.
  • the compounds of the present invention can also be administered in the form of liposomes.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.W., p. 33 et seq (1976).
  • the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more other agents used in the treatment of disorders.
  • Representative agents useful in combination with the compounds of the invention for the treatment of viral infections include, for example, Interferon, Ribavirin, and the like.
  • the additional active agents may generally be employed in therapeutic amounts as indicated in the Physicians' Desk Reference (PDR) 57th Edition (2003), PDR/Medical Economics Company, which is incorporated herein by reference, or such therapeutically useful amounts as would be known to one of ordinary skill in the art.
  • the compounds of the invention and the other therapeutically active agents can be administered at the recommended maximum clinical dosage or at lower doses. Dosage levels of the active compounds in the compositions of the invention may be varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient.
  • the combination can be administered as separate compositions or as a single dosage form containing both agents.
  • the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.
  • the mixture was purified on silica gel to give 4-substituted 2,5-difluorobenzenecarbonitrile.
  • HPLC solvents were from Burdick and Jackson (Muskegan, Michigan), or Fisher Scientific (Pittsburg, Pennsylvania). In some instances, purity was assessed by thin layer chromatography (TLC) using glass or plastic backed silica gel plates, such as, for example, Baker-Flex Silica Gel 1B2-F flexible sheets. TLC results were readily detected visually under ultraviolet light, or by employing well known iodine vapor and other various staining techniques.
  • Mass spectrometric analysis was performed on one of two LCMS instruments: a Waters System (Alliance HT HPLC and a Micromass ZQ mass spectrometer; Column: Eclipse XDB-C18, 2.1 x 50 mm; solvent system: 5-95% (or 35-95%, or 65-95% or 95-95%) acetonitrile in water with 0.05%TFA; flow rate 0.8 mL/min; molecular weight range 500- 1500; cone Voltage 20 V; column temperature 40°C) or a Hewlett Packard System (Series 1100 HPLC; Column: Eclipse XDB-C18, 2.1 x 50 mm; solvent system: 1-95% acetonitrile in water with 0.05%TFA; flow rate 0.4 mL/min; molecular weight range 150-850; cone Voltage 50 V; column temperature 30°C). All masses are reported as those of the protonated parent ions.
  • Preparative separations were carried out using a Flash 40 chromatography system and KP-Sil, 60A (Biotage, Charlottesville, Virginia), or by flash column chromatography using silica gel (230-400 mesh) packing material, or by HPLC using a C-18 reversed phase column.
  • Typical solvents employed for the Flash 40 Biotage system and flash column chromatography were dichloromethane, methanol, ethyl acetate, hexane, acetone, aqueous hydroxyamine and triethyl amine.
  • HPLC were varying concentrations of acetonitrile and water with 0.1 % trifluoroacetic acid.
  • Example compounds of Table 1 were synthesized and assayed as described above. Each of these Example compounds displayed an IC 50 value of less than 10 ⁇ M with respect to HCV. Many of the compounds displayed an IC 50 value of less than or equal to 1 ⁇ M or less than or equal to 0.1 ⁇ M. Many of these compounds exhibited IC 50 values of less than or equal to 0.050 ⁇ M, less than or equal to 0.030 ⁇ M, less than or equal to 0.025 ⁇ M, or less than or equal to 0.010 ⁇ M. For this reason, each of the R groups of any of the Example compounds is preferred.
  • each of these compounds is individually preferred and is preferred as a member of a group that includes any or all of the other compounds and each Example compound is preferred in methods of inhibiting HCV and in methods of treating biological conditions mediated by HCV activity, as well as modulating immunopotentiation to be used as a vaccine adjuvant.
  • Each of the Example compounds is also preferred for use in preparation of medicaments for vaccine adjuvants, , immunopotentiation, inhibiting HCV and in treating biological conditions mediated therefrom.
  • Candidate small molecule immuno-potentiators can be identified in vitro.
  • thiosemicarbazone was tested at concentrations of 10 ⁇ M, 5 ⁇ M, 2.5 ⁇ M, and 1.25 ⁇ M for its ability to induce cytokines from human PBMC.
  • Multi- cytokine analysis was performed using the Luminex system on culture supematants following 18 h incubation with the compound. The results are presented as percent of cytokine production following stimulation with an optimal does (10 ng/ml) of LPS.
  • the cytokines measured were: IL-6, TNF- ⁇ , IFN- ⁇ , and IL-10.
  • SMIPs Attention is drawn to Figure 3. Various compounds were evaluated for their ability to produce cytokines in response to the small molecule compounds using a modified sandwich ELISA. Compounds are screened for their TNF inducing. "Hits" are selected based on their TNF -inducing activity relative to an optimal dose a strong TNF inducer. The robustness of the assay and low backgrounds have allowed for the routine selection of hits with -10% of this activity which is normally between 5-10X background (cells alone).
  • Selected hits are then subjected to confirmation for their ability to induce cytokines from multiple donors at decreasing concentrations. Those compounds with consistent activity at or below 5 ⁇ M are considered confirmed.
  • Thiosemicarbazones compounds with and without anti-HCV activity were screened for their capacity to activate immune cells. Structural analogs of this scaffold have been tested for their ability to induce cytokines from human PBMC and murine splenocytes.
  • Figure 4 shows results from representative assays for human TNF-alpha (black bars) and IL-12 p40 (gray bars) presented as the % of LPS (1 ⁇ g/ml) activity. All compounds were tested at a final concentration of 5 ⁇ M except for poly I:C (PIC) and the 1806 oligodinucleotide (CpG) which were used at 10 ⁇ g/ml and 10 ng/ml respectively.
  • PIC poly I:C
  • CpG 1806 oligodinucleotide
  • Example 29 possess both SMIP and anti-HCV activity in independent assays.
  • RNA lines including Huh-11-7 or Huh 9-13, harboring HCV replicons (Lohmann, et al 3 Science 285:110-113, 1999) are seeded at 5x10 cells/well in 96 well plates and fed media containing DMEM (high glucose), 10% fetal calf serum, penicillin-streptomycin and non- essential amino acids. Cells are incubated in a 5% CO 2 incubator at 37 °C. At the end of the incubation period, total RNA is extracted and purified from cells using Qiagen Rneasy 96 Kit (Catalog No. 74182).
  • primers specific for HCV mediate both the reverse transcription (RT) of the HCV RNA and the amplification of the cDNA by polymerase chain reaction (PCR) using the TaqMan One-Step RT-PCR Master Mix Kit (Applied Biosystems catalog no. 4309169).
  • PCR polymerase chain reaction
  • the nucleotide sequences of the RT-PCR primers, which are located in the NS5B region of the HCV genome, are the following: [0373] HCV Forward primer "RBNS5bfor"
  • SDS Sequence Detection System
  • the increase in the amount of fluorescence is measured during each cycle of PCR and reflects the increasing amount of RT- PCR product.
  • quantification is based on the threshold cycle, where the amplification plot crosses a defined fluorescence threshold. Comparison of the threshold cycles of the sample with a known standard provides a highly sensitive measure of relative template concentration in different samples (ABI User Bulletin #2 December 11, 1997).
  • the data is analyzed using the ABI SDS program version 1.7.
  • the relative template concentration can be converted to RNA copy numbers by employing a standard curve of HCV RNA standards with known copy number (ABI User Bulletin #2 December 11, 1997).
  • the RT-PCR product was detected using the following labeled probe:
  • FAM Fluorescence reporter dye
  • TAMRA Quencher dye.
  • the RT reaction is performed at 48 °C for 30 minutes followed by PCR.
  • Detection System were: one cycle at 95 °C, 10 minutes followed by 35 cycles each of which included one incubation at 95 °C for 15 seconds and a second incubation for 60 °C for 1 minute.
  • GAPDH messenger RNA glyceraldehydes-3 -phosphate dehydrogenase
  • GAPDH RT-PCR is performed on the same exact RNA sample from which the HCV copy number is determined.
  • the GAPDH primers and probes, as well as the standards with which to determine copy number, is contained in the ABI Pre-Developed TaqMan Assay Kit
  • cells were seeded at 5x 103 cells/well in a 96 well plate and were incubated either with: 1) media containing 1% DMSO (0% inhibition control), 2) 100 international units, IU/ml Interferon-alpha 2b in media/1 %DMSO or 3) media/1 %DMSO containing a fixed concentration of compound.
  • 96 well plates as described above were then incubated at 37 °C for 3 days (primary screening assay) or 4 days (IC 50 determination).
  • C2 the ratio of HCV RNA copy number/GAPDH RNA copy number in the
  • the dose-response curve of the inhibitor was generated by adding compound in serial, three-fold dilutions over three logs to wells starting with the highest concentration of a specific compound at lOuM and ending with the lowest concentration of 0.01 uM. Further dilution series (luM to O.OOluM for example) was performed if the IC 5 o value was not in the linear range of the curve.
  • A, B and C values are expressed as the ratio of HCV RNA/GAPDH RNA as determined for each sample in each well of a 96 well plate as described above. For each plate the average of 4 wells were used to define the 100% and 0% inhibition values.
  • R dimethylamine, N-methyl-piperazine, N-iPr-piperazine
  • R' various piperazine and piperidine derivatives
  • the cmde reaction was purified by prep. HPLC.
  • the cmde reaction was passed through a Teflon syringe filter, and the clear filtrate was injected on a preparative HPLC.
  • the purification used a 20x50 mm Ultro 120 Cl 8 column running a 22 ml/min 2% gradient (AcCN/water, 0.1% TFA) for 16 min.
  • the purified fractions were lyophilized to dryness to give 3.2 mg of pure product as the TFA salt (14% yield and 87% purity).
  • IC 5 o values of less than or equal to 0.050 ⁇ M, less than or equal to 0.030 ⁇ M, less than or equal to 0.025 ⁇ M, or less than or equal to 0.010 ⁇ M.
  • the compounds are well-suited for use in the methods described herein.

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Abstract

L'invention concerne de nouveaux immunostimulants, de nouveaux adjuvants de vaccins, de nouveaux composés et de nouvelles compositions pharmaceutiques, ainsi que de nouvelles méthodes de traitement d'infections virales, y compris le VHC, par administration desdits composés et compositions, et de nouvelles méthodes de modulation de la réponse immune par administration de ces composés et/ou compositions.
PCT/US2003/041493 2002-12-27 2003-12-29 Thiosemicarbazones antiviraux et immunostimulants Ceased WO2004060308A2 (fr)

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AU2003300021A AU2003300021A1 (en) 2002-12-27 2003-12-29 Thiosemicarbazones as anti-virals and immunopotentiators
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EP2007765B1 (fr) * 2006-03-23 2012-06-27 Novartis AG Composes de potentialisation immunitaire
US12329902B2 (en) 2013-08-22 2025-06-17 Sipnose Ltd. Drug delivery devices and methods for administering substances to a body cavity by heterogenous aerosolization
DE202013105715U1 (de) 2013-08-22 2014-02-19 Sipnose Ltd. Vorrichtung zur Abgabe einer vorbestimmten Menge einer Substanz an eine natürliche Öffnung des Körpers
US11278682B2 (en) 2014-11-09 2022-03-22 Sipnose Ltd. Device and method for aerosolized delivery of substance to a natural orifice of the body
US11471618B2 (en) 2014-11-09 2022-10-18 Sipnose Ltd. Adjustable dosing delivery and multi sectioned drug compartment
US11116914B2 (en) 2014-11-09 2021-09-14 Sipnose Ltd. Device and method for aerosolized delivering of substance to a natural orifice of the body
US11992604B2 (en) 2014-11-09 2024-05-28 Sipnose Ltd. Devices and methods for delivering a substance to a body cavity
WO2015157242A1 (fr) * 2014-04-07 2015-10-15 H. Lee Moffitt Cancer Center And Research Institute, Inc. Inhibiteurs thiosemicarbazones de l'acide lysophosphatidique acyltransférase et leurs utilisations
US10722489B2 (en) * 2016-10-31 2020-07-28 Peking University D-3-phosphoglycerate dehydrogenase allosteric inhibitor and use thereof
EP3608326A1 (fr) * 2018-08-10 2020-02-12 Irbm S.P.A. Inhibiteurs tricycliques du virus de l'hépatite b
CN116349692A (zh) * 2023-03-30 2023-06-30 南京农业大学三亚研究院 一种促进根系生长的植物调节剂及其应用
CN116789622A (zh) * 2023-05-26 2023-09-22 青岛睿吉医疗技术有限公司 一种fxr调节剂及其制备方法与应用
CN119606955A (zh) * 2024-11-13 2025-03-14 南方医科大学 Txd-174在制备治疗和/或预防黄病毒属病毒感染产品中的应用

Family Cites Families (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US176503A (en) * 1876-04-25 Improvement in making endless woven fabrics
US45568A (en) * 1864-12-20 Improved apparatus for vaporizing and aerating volatile hydrocarbon
GB702093A (en) * 1950-10-11 1954-01-06 Bayer Ag New benzaldehyde thiosemicarbazones
DE1543591A1 (de) * 1951-01-28 1971-11-25 Hoechst Ag Verfahren zur Herstellung von Thiophen-2-aldehyd-thiosemicarbazonen
US3379620A (en) 1965-04-01 1968-04-23 Sterling Drug Inc Process for producing 4-aminobenzyl alcohol derivatives
US3499004A (en) * 1966-05-25 1970-03-03 Hoechst Ag Thiophene-2-aldehyde-thiosemicarbazone
US3980774A (en) 1969-03-20 1976-09-14 American Home Products Corporation Method of viral chemoprophylaxis and compounds therefor
GB1314899A (en) 1970-07-28 1973-04-26 Sterling Winthrop Group Ltd Thiosemicarbazones processes for their preparations and compositions incorporating them
US3917703A (en) 1972-01-26 1975-11-04 Sterling Drug Inc 4-(Aminoalkylamino)-2-halobenzyl lower-alkyl ethers
GB1507957A (en) 1975-03-25 1978-04-19 Byk Gulden Lomberg Chem Fab Nitrofuryl-pyrazole derivatives methods for producing them and medicaments comprising them
US4596798A (en) * 1982-03-30 1986-06-24 The United States Of America As Represented By The Secretary Of The Army 2-acetylpyridine thiosemicarbazones as antiviral agents
EP0258182A1 (fr) 1986-08-08 1988-03-02 Sandoz Ag Semi-carbazones et thiosemi-carbazones
US4963354A (en) * 1987-01-21 1990-10-16 Genentech, Inc. Use of tumor necrosis factor (TNF) as an adjuvant
US5204352A (en) 1987-09-29 1993-04-20 The United States Of America As Represented By The Secretary Of The Army Compounds exhibiting anti-parasitic activity and a method for their use
US4971986A (en) 1988-03-25 1990-11-20 Ciba-Geigy Corporation Arylhydrazones useful as SAMDC inhibitors
US5019560A (en) 1988-10-03 1991-05-28 Bayer Ag Method for treating fungal infections with nikkomycin derivatives
US5278152A (en) 1989-12-21 1994-01-11 Hoechst Aktiengesellschaft 2-formylbenzylphosphonic acid derivatives useful for the treatment of diseases caused by viruses
EP0457727A1 (fr) 1990-05-17 1991-11-21 Ciba-Geigy Ag Pesticides
DE4331448A1 (de) 1993-09-16 1995-03-23 Hoechst Schering Agrevo Gmbh Substituierte Isoxazoline, Verfahren zu deren Herstellung, diese enthaltende Mittel und deren Verwendung als Safener
DE4425612A1 (de) 1994-07-20 1996-04-04 Bayer Ag 6-gliedrige stickstoffhaltige Heteroaryl-oxazolidinone
US6350771B1 (en) 1996-12-24 2002-02-26 Rhone-Poulenc, Inc. Pesticidal 1-arylpyrazoles
DE69829048T2 (de) 1997-04-22 2006-02-09 Euro-Celtique S.A. Die verwendung von durch carbozyklische und heterozyklische reste substituierte semicarbazonen und thiosemicarbazonen als natriumkanalblocker
AU1179000A (en) 1998-11-19 2000-06-13 Shionogi & Co., Ltd. Preventives and/or remedies for central nervous system diseases containing compounds having TXA2 receptor antagonism and/or TXA2 synthase inhibitory effect
US6329378B1 (en) 1999-02-10 2001-12-11 Anadys Pharmaceuticals, Inc. Hydrazone, hydrazine and thiosemicarbazone derivatives as antifungal agents
JP2003513965A (ja) 1999-11-05 2003-04-15 スミスクライン・ビーチャム・コーポレイション セミカルバゾン誘導体およびそれらのトロンボポエチン模倣物としての使用
FR2803225B1 (fr) 1999-12-29 2002-06-14 Biomerieux Sa Appareil d'analyse a compartiment reactionnel a geometrie variable, procede de mixage et de guidage de liquides
DE60133758T2 (de) 2000-10-26 2009-07-02 Amgen Inc., Thousand Oaks Antiphlogistische mittel
US20030176503A1 (en) 2001-04-20 2003-09-18 Sergio Altamura Treating hepatitis C viral infections with thiosemicarbazone compounds
US20030045568A1 (en) 2001-04-20 2003-03-06 Sergio Altamura Treating hepatitis C viral infections with thiosemicarbazone compounds
CN100544718C (zh) * 2001-04-20 2009-09-30 维奥恩药品公司 化合物在制备抗病毒剂中的用途

Cited By (121)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2272531A2 (fr) 2004-04-30 2011-01-12 Novartis Vaccines and Diagnostics S.r.l. Intégration du vaccin conjugué de méningococcus
EP2848692A1 (fr) 2004-05-21 2015-03-18 Novartis Vaccines and Diagnostics, Inc. Vecteurs d'alphavirus de vaccins contre le virus de la grippe
EP2811027A1 (fr) 2004-05-21 2014-12-10 Novartis Vaccines and Diagnostics, Inc. Vecteurs alphavirus pour vaccins contre le VRS et le PIV
JP2008516959A (ja) * 2004-10-18 2008-05-22 イーライ リリー アンド カンパニー ｍＧｌｕＲ３受容体アンタゴニストとして用いるための１−（ヘテロ）アリール−３−アミノ−ピロリジン誘導体
EP2193810A1 (fr) 2005-01-14 2010-06-09 Novartis Vaccines and Diagnostics S.r.l. Vaccin conjugué contre le meningocoque
EP3498302A1 (fr) 2005-02-01 2019-06-19 Novartis Vaccines and Diagnostics S.r.l. Conjugaison de saccharides capsulaires streptococciques
EP2298795A1 (fr) 2005-02-18 2011-03-23 Novartis Vaccines and Diagnostics, Inc. Immunogènes d'E. coli uropathogène
EP2351772A1 (fr) 2005-02-18 2011-08-03 Novartis Vaccines and Diagnostics, Inc. Protéines et acides nucléiques d'Escherichia coli associé à la méningite/sepsie
EP2614709A1 (fr) 2005-07-18 2013-07-17 Novartis AG Petit modèle d'animal pour une réplication du VHC
EP2357000A1 (fr) 2005-10-18 2011-08-17 Novartis Vaccines and Diagnostics, Inc. Immunisations mucosiques et systémiques avec des particules de réplicon à alpha-virus
EP3714900A1 (fr) 2005-11-04 2020-09-30 Seqirus UK Limited Vaccins avec adjuvants dotés d'antigènes non virions préparés à partir de virus de la grippe cultivés dans une culture cellulaire
EP2368573A2 (fr) 2005-11-04 2011-09-28 Novartis Vaccines and Diagnostics S.r.l. Vaccins contre la grippe incluant des combinaisons d'adjuvants particulaires et d'immunopotentiateurs
EP2368572A2 (fr) 2005-11-04 2011-09-28 Novartis Vaccines and Diagnostics S.r.l. Vaccins avec adjuvants dotés d'antigènes non virions préparés à partir de virus de la grippe cultivés dans une culture cellulaire
EP2377552A2 (fr) 2005-11-04 2011-10-19 Novartis Vaccines and Diagnostics S.r.l. Vaccins contre la grippe dotés d'une quantité réduite d'adjuvant d'émulsion
EP2377551A2 (fr) 2005-11-04 2011-10-19 Novartis Vaccines and Diagnostics S.r.l. Vaccins contre la grippe avec adjuvants incluant des agents induits par cytokine
EP2360175A2 (fr) 2005-11-22 2011-08-24 Novartis Vaccines and Diagnostics, Inc. Particules de type virus (VLPs) de norovirus et de sapovirus
EP2261223A1 (fr) 2006-01-20 2010-12-15 Novartis AG Derives de pyrimidine utilises en tant qu inhibiteurs de kinase pi-3
EP3753574A1 (fr) 2006-01-27 2020-12-23 Seqirus UK Limited Vaccins contre la grippe contenant de l'hémagglutinine et des protéines de matrice
EP2478916A1 (fr) 2006-01-27 2012-07-25 Novartis Vaccines and Diagnostics GmbH Vaccins contre la grippe contenant de l'hémagglutinine et des protéines de matrice
EP2357184A1 (fr) 2006-03-23 2011-08-17 Novartis AG Composés d'imidazoquinoxaline en tant qu'immunomodulateurs
EP2382987A1 (fr) 2006-03-24 2011-11-02 Novartis Vaccines and Diagnostics GmbH Stockage de vaccins contre la grippe sans réfrigération
EP2382988A1 (fr) 2006-03-31 2011-11-02 Novartis AG Immunisation mucosique et parentérale contre le VIH
US7932262B2 (en) 2006-04-06 2011-04-26 Novartis Ag Quinazolines for PDK1 inhibition
WO2008020335A2 (fr) 2006-06-09 2008-02-21 Novartis Ag Compositions immunogènes pour streptococcus agalactiae
EP2514437A1 (fr) 2006-07-20 2012-10-24 Novartis AG Stockage congelé de vaccins contre la grippe
EP2586790A2 (fr) 2006-08-16 2013-05-01 Novartis AG Immunogènes d'Escherischia coli pathogènes des voies urinaires
EP3456348A1 (fr) 2006-09-11 2019-03-20 Seqirus UK Limited Fabrication de vaccins contre le virus de la grippe sans utiliser d' ufs
EP2497495A2 (fr) 2006-09-11 2012-09-12 Novartis AG Fabrication de vaccins contre la grippe sans utiliser d'oeufs
EP2532362A1 (fr) 2006-12-06 2012-12-12 Novartis AG Vaccins comprenant un antigène issu de quatre souches du virus grippal
EP2679240A1 (fr) 2006-12-06 2014-01-01 Novartis AG Vaccins comprenant un antigène issu de quatre souches du virus grippal
EP2548895A1 (fr) 2007-01-11 2013-01-23 Novartis AG Saccharides modifiés
EP2484377A1 (fr) 2007-06-27 2012-08-08 Novartis AG Vaccins contre la grippe pauvre en additifs
US9463250B2 (en) 2007-07-17 2016-10-11 Glaxosmithkline Biologicals Sa Conjugate purification
EP2659912A2 (fr) 2007-07-17 2013-11-06 Novartis AG Purification de conjugué
EP2572726A1 (fr) 2007-08-01 2013-03-27 Novartis AG Compositions comprenant des antigènes pneumocoques
WO2009034473A2 (fr) 2007-09-12 2009-03-19 Novartis Ag Antigènes mutants gas57 et anticorps gas57
EP2614835A1 (fr) 2007-11-26 2013-07-17 Novartis AG Vaccination par de multiples clades du virus de la grippe A h5
EP3067048A1 (fr) 2007-12-07 2016-09-14 Novartis Ag Compositions d'induction des réponses immunitaires
EP2891498A1 (fr) 2007-12-20 2015-07-08 Novartis AG Procédés de fermentation pour cultiver des streptocoques et procédés de purification pour obtenir des CPS à partir de ceux-ci
WO2009080694A1 (fr) 2007-12-20 2009-07-02 Novartis Ag Dérivés de thiazole utilisés comme inhibiteur de la pi 3 kinase
EP2537857A2 (fr) 2007-12-21 2012-12-26 Novartis AG Formes mutantes de streptolysine O
WO2009103022A1 (fr) * 2008-02-13 2009-08-20 Itherx Pharmaceuticals, Inc. Dérivés de cycloindoles à cycle condensé substitué et leurs procédés d’utilisation
EP2101173A1 (fr) 2008-03-14 2009-09-16 Vivalis Procédé in vitro pour déterminer si un candidat destiné à un médicament pour une protéine cible est actif contre une variante de cette protéine
EP2889042A2 (fr) 2008-03-18 2015-07-01 Novartis AG Améliorations dans la préparation d'antigènes de vaccin contre le virus de la grippe
EP3459563A1 (fr) 2008-03-18 2019-03-27 Seqirus UK Limited Améliorations dans la préparation d'antigènes de vaccin contre le virus de la grippe
FR2932480A1 (fr) * 2008-06-16 2009-12-18 Sanofi Aventis Phenyl-alkyl-piperazines ayant une activite modulatrice du tnf
JP2011524409A (ja) * 2008-06-16 2011-09-01 サノフイ−アベンテイス Ｔｎｆの調節活性を有するフェニル−アルキルピペラジン
US8153637B2 (en) 2008-06-16 2012-04-10 Sanofi Phenyl-alkyl piperazines having TNF-modulating activity, preparation method, and therapeutic use thereof
CN102123995A (zh) * 2008-06-16 2011-07-13 赛诺菲-安万特 具有tnf调节活性的苯基-烷基哌嗪
WO2009153514A1 (fr) * 2008-06-16 2009-12-23 Sanofi-Aventis Phenyl-alkyl piperazines ayant une activite modulatrice du tnf
CN105198803A (zh) * 2008-06-16 2015-12-30 赛诺菲-安万特 具有tnf调节活性的苯基-烷基哌嗪
FR2940288A1 (fr) * 2008-12-23 2010-06-25 Sanofi Aventis Phenyl-alkyl-piperazines ayant une activite modulatrice du tnf
WO2010079464A1 (fr) 2009-01-12 2010-07-15 Novartis Ag Antigènes à domaines cna_b dans des vaccins contre des bactéries à gram positif
WO2010100632A2 (fr) 2009-03-06 2010-09-10 Novartis Ag Antigènes de chlamydia
EP3549602A1 (fr) 2009-03-06 2019-10-09 GlaxoSmithKline Biologicals S.A. Antigènes de chlamydia
EP2510947A1 (fr) 2009-04-14 2012-10-17 Novartis AG Compositions pour l'immunisation contre le staphylococcus aureus
EP3263128A2 (fr) 2009-04-14 2018-01-03 GlaxoSmithKline Biologicals S.A. Compositions pour l'immunisation contre staphylococcus aureus
USH2283H1 (en) 2009-04-27 2013-09-03 Novartis Ag Vaccines for protecting against influenza
USH2284H1 (en) 2009-04-27 2013-09-03 Novartis Ag Vaccines for protecting against influenza
WO2011000905A1 (fr) 2009-07-02 2011-01-06 Novartis Ag 2-carboxamide cycloamino urées substituées
WO2011004263A2 (fr) 2009-07-07 2011-01-13 Novartis Ag Immunogènes d' escherichia coli conservés
EP4183412A1 (fr) 2009-07-15 2023-05-24 GlaxoSmithKline Biologicals S.A. Compositions à base de protéine f du vrs et procédés de fabrication associés
EP3178490A2 (fr) 2009-07-15 2017-06-14 GlaxoSmithKline Biologicals S.A. Compositions à base de protéine f du vrs et procédés de fabrication associés
EP4218799A1 (fr) 2009-07-15 2023-08-02 GlaxoSmithKline Biologicals S.A. Compositions de protéine f rsv et leurs procédés de fabrication
EP4218800A1 (fr) 2009-07-15 2023-08-02 GlaxoSmithKline Biologicals S.A. Compositions de protéine f rsv et leurs procédés de fabrication
WO2011008974A2 (fr) 2009-07-15 2011-01-20 Novartis Ag Compositions à base de protéine f du vrs et procédés de fabrication associés
EP3988115A2 (fr) 2009-07-15 2022-04-27 GlaxoSmithKline Biologicals S.A. Compositions à base de protéine f du vrs et procédés de fabrication associés
WO2011007257A1 (fr) 2009-07-16 2011-01-20 Novartis Ag Immunogènes d'escherichia coli détoxifiés
EP2837386A1 (fr) 2009-07-16 2015-02-18 Novartis AG Immunogènes d'escherichia coli détoxifiés
WO2011138636A1 (fr) 2009-09-30 2011-11-10 Novartis Ag Conjugaison de polysaccharides capsulaires de staphylococcus aureus de type 5 et de type 8
WO2011048561A1 (fr) 2009-10-20 2011-04-28 Novartis Ag Procédés diagnostiques et thérapeutiques pour une maladie cardiaque rhumatismale basés sur des marqueurs de streptocoque de groupe a
WO2011058302A1 (fr) 2009-11-10 2011-05-19 Guy's And St Thomas's Nhs Foundation Trust Antigène associé à la bactériémie à partir de staphylococcus aureus
WO2011080595A2 (fr) 2009-12-30 2011-07-07 Novartis Ag Immunogènes de polysaccharide conjugués à des protéines porteuses de e. coli
WO2011130379A1 (fr) 2010-04-13 2011-10-20 Novartis Ag Compositions de benzonapthyridine et leurs utilisations
WO2011149564A1 (fr) 2010-05-28 2011-12-01 Tetris Online, Inc. Infrastructure de jeu informatique asynchrone hybride interactif
WO2011161551A2 (fr) 2010-06-11 2011-12-29 Novartis Ag Vaccins à base de vésicules membranaires
EP3399021A1 (fr) 2010-06-11 2018-11-07 GlaxoSmithKline Biologicals S.A. Vaccins d'omv
WO2012006359A1 (fr) 2010-07-06 2012-01-12 Novartis Ag Délivrance d'arn auto-répliquant en utilisant des particules polymères biodégradables
EP3611269A1 (fr) 2010-07-06 2020-02-19 GlaxoSmithKline Biologicals SA Administration d' arn autoreplicatif en utilisant des particules de polymères biodégradables
WO2012016970A1 (fr) 2010-08-02 2012-02-09 Novartis Ag Forme cristalline de 1-(4-méthyl-5-[2-(2,2,2-trifluoro-1,1-diméthyléthyl)-pyridine-4-yl]-thiazol-2-yl)-amide du 2-amide de l'acide (s)-pyrrolidine-1,2-dicarboxylique et son utilisation comme inhibiteur de pi3k
WO2012035519A1 (fr) 2010-09-16 2012-03-22 Novartis Ag Compositions immunogènes
WO2012085668A2 (fr) 2010-12-24 2012-06-28 Novartis Ag Composés
EP4144368A1 (fr) 2011-01-26 2023-03-08 GlaxoSmithKline Biologicals S.A. Régime d'immunisation contre le vrs
EP3527224A1 (fr) 2011-01-26 2019-08-21 GlaxoSmithKline Biologicals S.A. Régime d'immunisation contre le vrs
WO2012103361A1 (fr) 2011-01-26 2012-08-02 Novartis Ag Régime d'immunisation contre le vrs
EP4159232A1 (fr) 2011-01-26 2023-04-05 GlaxoSmithKline Biologicals S.A. Régime d'immunisation contre le vrs
WO2012104776A1 (fr) 2011-01-31 2012-08-09 Novartis Ag Dérivés hétérocycliques inédits
EP3275892A2 (fr) 2011-05-13 2018-01-31 GlaxoSmithKline Biologicals S.A. Antigènes f de rsv pré-fusion
WO2012158613A1 (fr) 2011-05-13 2012-11-22 Novartis Ag Antigènes de pré-fusion f du vrs
EP3854413A1 (fr) 2011-07-06 2021-07-28 GlaxoSmithKline Biologicals SA Compositions de combinaisons immunogènes et utilisations de celles-ci
WO2013006838A1 (fr) 2011-07-06 2013-01-10 Novartis Ag Compositions de combinaisons immunogènes et utilisations de celles-ci
EP3332802A1 (fr) 2011-07-06 2018-06-13 GlaxoSmithKline Biologicals SA Compositions de combinaisons immunogènes et utilisations de celles-ci
WO2013006842A2 (fr) 2011-07-06 2013-01-10 Novartis Ag Compositions immunogènes et leurs utilisations
WO2013009564A1 (fr) 2011-07-08 2013-01-17 Novartis Ag Procédé de ligature de la tyrosine
WO2013061305A1 (fr) 2011-10-28 2013-05-02 Novartis Ag Nouveaux dérivés de purine et utilisation de ceux-ci dans le traitement d'une maladie
WO2013068949A1 (fr) 2011-11-07 2013-05-16 Novartis Ag Molécule porteuse comprenant un antigène spr0096 et un antigène spr2021
WO2013108272A2 (fr) 2012-01-20 2013-07-25 International Centre For Genetic Engineering And Biotechnology Vaccin antipaludique ciblant le stade sanguin
WO2013173283A1 (fr) 2012-05-16 2013-11-21 Novartis Ag Régime posologique pour un inhibiteur de pi-3 kinase
WO2013174832A1 (fr) 2012-05-22 2013-11-28 Novartis Ag Conjugué de sérogroupe x de méningocoque
US10124051B2 (en) 2012-05-22 2018-11-13 Glaxosmithkline Biologicals Sa Meningococcus serogroup X conjugate
WO2014005958A1 (fr) 2012-07-06 2014-01-09 Novartis Ag Compositions immunogéniques et leurs utilisations
WO2014053521A2 (fr) 2012-10-02 2014-04-10 Novartis Ag Conjugués saccharidiques non linéaires
EP3482770A1 (fr) 2012-10-03 2019-05-15 GlaxoSmithKline Biologicals S.A. Compositions immunogènes
WO2014053607A1 (fr) 2012-10-03 2014-04-10 Novartis Ag Compositions immunogènes
WO2014053612A1 (fr) 2012-10-03 2014-04-10 Novartis Ag Composition immunogène
EP3345617A1 (fr) 2012-11-30 2018-07-11 GlaxoSmithKline Biologicals S.A. Antigènes de pseudomonas et combinaisons d'antigènes
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WO2015068129A1 (fr) 2013-11-08 2015-05-14 Novartis Ag Vaccins conjugués contre la salmonelle
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US10252987B2 (en) * 2015-08-18 2019-04-09 Institute Of Medicinal Biotechnology, Chinese Academy Of Medical Sciences Type of antiviral compound
WO2017028472A1 (fr) * 2015-08-18 2017-02-23 中国医学科学院医药生物技术研究所 Nouveau type de composé antiviral
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WO2018060833A1 (fr) 2016-09-27 2018-04-05 Novartis Ag Schéma posologique pour l'alpelisib, un inhibiteur de la phosphatidylinositol 3-kinase spécifique de l'isoforme alpha
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